Analogues and derivatives of cephalotaxine and methods for making and using the compounds

Abstract

Disclosed herein are embodiments of a compound having a Formula Ior a salt, solvate, N-oxide, prodrug, diastereomer or enantiomer thereof. Also disclosed are derivative compounds made from the compound of Formula I. Certain derivative compounds have a Formula V-2, or a salt, solvate, N-oxide, prodrug, diastereomer or enantiomer thereof.Also disclosed are method for making and using the disclosed compounds. Certain disclosed embodiments are useful for treating and/or preventing certain diseases and/or disorders, including proliferation diseases, such as leukemia.

We claim: 
     
       1. A compound having a formula 
       
         
           
           
               
               
           
         
       
       or a salt, solvate, N-oxide, diastereomer or enantiomer thereof, wherein:
 x is from 0 to 4; 
 each R 1  independently is hydroxyl, halogen, aliphatic, alkoxy, haloalkyl, amino, protected amino, carboxylic ester, or two R 1 s, together with the atoms to which they are attached, form an aryl or heterocyclyl; 
 each of R 2 , R 3 , R 4  and R 5  independently is H, halogen, aliphatic, hydroxyalkyl, protected hydroxyalkyl, aryl, heteroaryl, hydroxyl, protected hydroxyl, haloalkyl, amino, protected amino, carboxylic ester, or two of R 2 , R 3 , R 4  and R 5  that are attached to the same carbon together form ═O or ═S; and 
 each of Q 1  and Q 2  independently is aliphatic. 
 
     
     
       2. The compound of  claim 1 , wherein x is 2, 3, or 4. 
     
     
       3. The compound of  claim 1 , wherein two R 1 s together with the atoms to which they are attached, form an aryl or 5- or 6-membered heterocyclyl ring. 
     
     
       4. The compound of  claim 3 , wherein the 5- or 6-membered heterocyclyl is a pyridinyl, imidazolyl, pyrazolyl, pyrrolyl, oxazolyl, thiazolyl, furanyl, thiophenyl, 1,3-dioxole, 1,4-dioxine, 2,3-dihydro-1,4-dioxine, 1,4-oxazine, or 3,4-dihydro-1,4-oxazine. 
     
     
       5. The compound of  claim 1 , wherein the 
       
         
           
           
               
               
           
         
       
       moiety is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       6. The compound of  claim 1 , wherein the 
       
         
           
           
               
               
           
         
       
       moiety is 
       
         
           
           
               
               
           
         
       
     
     
       7. The compound of  claim 1 , wherein each of Q 1  and Q 2  independently is alkyl optionally substituted with 1, 2, 3, or 4 substituents from halogen, alkyl, hydroxyalkyl, protected hydroxyalkyl, ═O, ═S, aryl, hydroxyl, protected hydroxyl, haloalkyl, amino, protected amino, or carboxylic ester. 
     
     
       8. The compound of  claim 7 , wherein each of Q 1  and Q 2  independently is C 1-2  alkyl optionally substituted with 1, 2, 3, or 4 substituents from halogen, alkyl, hydroxyalkyl, protected hydroxyalkyl, ═O, ═S, aryl, hydroxyl, protected hydroxyl, haloalkyl, amino, protected amino, or carboxylic ester. 
     
     
       9. The compound of  claim 8 , 
       wherein one or more of the following applies:
 i) Q 1  is —CH 2 — or —CH 2 CH 2 —; 
 ii) Q 2  is —CH 2 — or —CH 2 CH 2 ; or 
 iii) Q 1  is —CH 2 — or —CH 2 CH 2 — and Q 2  is —CH 2 — or —CH 2 CH 2 . 
 
     
     
       10. The compound of  claim 8 , wherein one or both of the following applies:
 Q 1  is substituted with 1, 2, 3, or 4 substituents from methyl, ethyl, ═O, ═S, hydroxyl, phenyl, hydroxyethyl, hydroxypropyl, protected hydroxyalkyl, protected hydroxyl, or protected amino; 
 Q 2  is substituted with 1, 2, 3, or 4 substituents from Cl, methyl, ethyl, ═O, ═S, hydroxyl, protected hydroxyl, hydroxyethyl, hydroxypropyl, protected hydroxyalkyl, protected hydroxyl, or protected amino. 
 
     
     
       11. The compound of  claim 1 , wherein each of R 2 , R 3 , R 4  and R 5  independently is H, halogen, aliphatic, hydroxyalkyl, protected hydroxyalkyl, aryl, heteroaryl, hydroxyl, protected hydroxyl, or two of R 2 , R 3 , R 4  and R 5  that are attached to the same carbon together form ═O or ═S. 
     
     
       12. The compound of  claim 1 , wherein each of R 2 , R 3 , R 4  and R 5  is H. 
     
     
       13. The compound of  claim 1 , wherein the 
       
         
           
           
               
               
           
         
       
       moiety is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein PG is a hydroxyl protecting group. 
     
     
       14. The compound of  claim 13 , wherein PG is methoxymethyl (MOM), tert-butyl, iso-propyl, tert-butyldimethylsilyl (TBS or TBDMS), trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldiphenylsilyl (TBDPS), or triisopropylsilyl (TIPS). 
     
     
       15. The compound of  claim 1 , wherein the 
       
         
           
           
               
               
           
         
       
       moiety is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein PG is a hydroxyl protecting group. 
     
     
       16. The compound of  claim 15 , wherein PG is methoxymethyl (MOM), tert-butyl, iso-propyl, tert-butyldimethylsilyl (TBS or TBDMS), trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldiphenylsilyl (TBDPS), or triisopropylsilyl (TIPS). 
     
     
       17. The compound of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
       18. A method for making a compound of Formula I, comprising:
 i) treating a protected hydroxyl ketone of formula A-1 with a haloacetate ester of formula A-2 to form a compound of formula A-3 
 
       
         
           
           
               
               
           
         
         ii) treating the compound of formula A-3 with a protected amino compound of formula A-4 to form a compound of formula A-5 
       
       
         
           
           
               
               
           
         
         iii) converting the OPG moiety of A-5 to a leaving group in a compound of formula A-6 
       
       
         
           
           
               
               
           
         
       
       and
 iv) cyclizing A-6 to form the compound of Formula I, 
 
       
         
           
           
               
               
           
         
       
       or a salt, solvate, N-oxide, diastereomer or enantiomer thereof, wherein:
 each PG independently is a protecting group; 
 LG is a leaving group; 
 each X 1  independently is a halogen; 
 x is from 0 to 4; 
 R A  is alkyl; 
 if present, each R 1  independently is hydroxyl, halogen, aliphatic, alkoxy, haloalkyl, amino, protected amino, carboxylic ester, or two R 1 s, together with the atoms to which they are attached, form an aryl or heterocyclyl; 
 each of R 2 , R 3 , R 4  and R 5  independently is H, halogen, aliphatic, hydroxyalkyl, protected hydroxyalkyl, aryl, heteroaryl, hydroxyl, protected hydroxyl, haloalkyl, amino, protected amino, carboxylic ester, or two of R 2 , R 3 , R 4  and R 5  that are attached to the same carbon together form ═O or =S; and 
 each of Q 1  and Q 2  independently is aliphatic. 
 
     
     
       19. The method of  claim 18 , wherein one or more of the following applies:
 i) each PG independently is trifluoroacetate or a silyl protecting group; 
 ii) LG is mesylate; 
 iii) X 1  is Cl; 
 iv) R A  is C 1-2  alkyl. 
 
     
     
       20. A method for making a compound of Formula (II), comprising:
 treating a compound of Formula I 
 
       
         
           
           
               
               
           
         
       
       or a salt, solvate, N-oxide, diastereomer or enantiomer thereof, with an oxidizing agent to form a racemic compound of Formula II 
       
         
           
           
               
               
           
         
       
       or a salt, solvate, or N-oxide thereof, wherein:
 x is from 0 to 4; 
 if present, each R 1  independently is hydroxyl, halogen, aliphatic, alkoxy, haloalkyl, amino, protected amino, carboxylic ester, or two R 1 s, together with the atoms to which they are attached, form an aryl or heterocyclyl; 
 each of R 2 , R 3 , R 4  and R 5  independently is H, halogen, aliphatic, hydroxyalkyl, protected hydroxyalkyl, aryl, heteroaryl, hydroxyl, protected hydroxyl, haloalkyl, amino, protected amino, carboxylic ester, or two of R 2 , R 3 , R 4  and R 5  that are attached to the same carbon together form ═O or =S; and 
 each of Q 1  and Q 2  independently is aliphatic. 
 
     
     
       21. The method of  claim 20 , wherein the oxidizing agent is DDQ. 
     
     
       22. The method of  claim 20 , further comprising:
 treating the racemic compound of Formula II with Ru(p-cymene)-(S,S)-TsDPEN, trimethylamine, and formic acid to form a compound of Formula A-7 and a (+)-compound of Formula II 
 
       
         
           
           
               
               
           
         
       
     
     
       23. The method of  claim 22 , further comprising treating the (+)-compound of Formula II with 2,2-dimethoxypropane and p-toluene sulfonic acid to form a second portion of racemic compound according to Formula II 
       
         
           
           
               
               
           
         
       
     
     
       24. The method of  claim 22 , wherein the compound of formula I is 
       
         
           
           
               
               
           
         
       
       and the compound of formula A-7 is 
       
         
           
           
               
               
           
         
       
     
     
       25. The method of  claim 18 , wherein R 2 , R 3 , R 4 , and R 5  are all H. 
     
     
       26. The method of  claim 18 , wherein:
 R 2 , R 3 , R 4 , and R 5  are all H; 
 Q 1  is —CH 2 CH 2 —; 
 Q 2  is —CH—; 
 the 
 
       
         
           
           
               
               
           
         
       
       moiety is 
       
         
           
           
               
               
           
         
       
       and 
       the compound of Formula I is